The histamine H4 receptor (H4R), sometimes also referred to simply as “H4” or “H4”, is the most recently identified receptor for histamine (for reviews, see: Fung-Leung, W.-P., et al., Curr. Opin. Invest. Drugs 2004, 5(11), 1174-1183; de Esch, I. J. P., et al., Trends Pharmacol. Sci. 2005, 26(9), 462-469; Zhang, M. et al. Pharmacol. Ther. 2007, 113, 594-606; Thurmond, R. L. et al. Nat. Rev. Drug Disc. 2008, 7, 41-53; Zhang, M. et al. Expert Opin. Investig. Drugs 2006, 15(11), 1443-1452). The receptor is found in the bone marrow and spleen and is expressed on eosinophils, basophils, mast cells (Liu, C., et al., Mol. Pharmacol, 2001, 59(3), 420-426; Morse, K. L., et al., J. Pharmacol. Exp. Ther. 2001, 296(3), 1058-1066; Hofstra, C. L., et al., J. Pharmacol. Exp. Ther. 2003, 305(3), 1212-1221; Lippert, U., et al., J. Invest. Dermatol. 2004, 123(1), 116-123; Voehringer, D., et al., Immunity 2004, 20(3), 267-277), CD8+ T cells (Gantner, F., et al., J. Pharmacol. Exp. Ther. 2002, 303(1), 300-307), dendritic cells, and human synovial cells from rheumatoid arthritis patients (Ikawa, Y., et al., Biol. Pharm. Bull. 2005, 28(10), 2016-2018). The histamine H4 receptor is also elevated in human nasal polyp tissue (Jókúti, A. et al. Cell. Biol. Int. 2007, 31, 1367-1370). However, expression in neutrophils and monocytes is less well defined (Ling, P., et al., Br. J. Pharmacol. 2004, 142(1), 161-171; Damaj, B. B. et al. J. Immunol. 2007, 179, 7907-7915). Receptor expression is at least in part controlled by various inflammatory stimuli (Coge, F., et al., Biochem. Biophys. Res. Commun. 2001, 284(2), 301-309; Morse, et al., 2001), thus supporting that H4 receptor activation influences inflammatory responses. Because of its preferential expression on immunocompetent cells, the H4 receptor is closely related with the regulatory functions of histamine during the immune response.
A biological activity of histamine in the context of immunology and autoimmune diseases is closely related with the allergic response and its deleterious effects, such as inflammation. Events that elicit the inflammatory response include physical stimulation (including trauma), chemical stimulation, infection, and invasion by a foreign body. The inflammatory response is characterized by pain, increased temperature, redness, swelling, reduced function, or a combination of these.
Mast cell degranulation (exocytosis) releases histamine and leads to an inflammatory response that may be initially characterized by a histamine-modulated wheal and flare reaction. A wide variety of immunological stimuli (e.g., allergens or antibodies) and non-immunological (e.g., chemical) stimuli may cause the activation, recruitment, and de-granulation of mast cells. Mast cell activation initiates allergic inflammatory responses, which in turn cause the recruitment of other effector cells that further contribute to the inflammatory response. It has been shown that histamine induces chemotaxis of mouse mast cells (Hofstra, et al., 2003). Chemotaxis does not occur using mast cells derived from H4 receptor knockout mice. Furthermore, the response is blocked by an H4-specific antagonist, but not by H1, H2 or H3 receptor antagonists (Hofstra, et al., 2003; Thurmond, R. L., et al., J. Pharmacol. Exp. Ther. 2004, 309(1), 404-413). The in vivo migration of mast cells to histamine has also been investigated and shown to be H4 receptor dependent (Thurmond, et al., 2004). The migration of mast cells may play a role in allergic rhinitis and allergy where increases in mast cell number are found (Kirby. J. G., et al., Am. Rev. Respir. Dis. 1987, 136(2), 379-383; Crimi, E., et al., Am. Rev. Respir. Dis. 1991, 144(6), 1282-1286; Amin, K., et al., Am. J. Resp. Crit. Care Med. 2000, 162(6), 2295-2301; Gauvreau, G. M., et al., Am. J. Resp. Crit. Care Med. 2000, 161(5), 1473-1478; Kassel, O., et al., Clin. Exp. Allergy 2001, 31(9), 1432-1440). In addition, it is known that in response to allergens there is a redistribution of mast cells to the epithelial lining of the nasal mucosa (Fokkens, W. J., et al., Clin. Exp. Allergy 1992, 22(7), 701-710; Slater, A., et al., J. Laryngol. Otol. 1996, 110, 929-933). These results show that the chemotactic response of mast cells to histamine is mediated by histamine H4 receptors.
It has been shown that eosinophils can chemotax towards histamine (O'Reilly, M., et al., J. Recept. Signal Transduction 2002, 22(1-4), 431-448; Buckland, K. F., et al., Br. J. Pharmacol. 2003, 140(6), 1117-1127; Ling et al., 2004). Using H4 selective ligands, it has been shown that histamine-induced chemotaxis of eosinophils is mediated through the H4 receptor (Buckland, et al., 2003; Ling et al., 2004). Cell surface expression of adhesion molecules, CD11b/CD18 (LFA-1) and CD54 (ICAM-1), on eosinophils increases after histamine treatment (Ling, et al., 2004). This increase is blocked by H4 receptor antagonists but not by H1, H2, or H3 receptor antagonists.
The H4R also plays a role in dendritic cells and T cells. In human monocyte-derived dendritic cells, H4R stimulation suppresses IL-12p70 production and drives histamine-mediated chemotaxis (Gutzmer, R., et al., J. Immunol, 2005, 174(9), 5224-5232). A role for the H4 receptor in CD8+ T cells has also been reported. Gantner, et al., (2002) showed that both H4 and H2 receptors control histamine-induced IL-16 release from human CD8+ T cells. IL-16 was found in the bronchoalveolar fluid of allergen- or histamine-challenged asthmatics (Mashikian, V. M., et al., J. Allergy Clin. Immunol. 1998, 101 (6, Part 1), 786-792; Krug, N., et al., Am. J. Resp. Crit. Care Med. 2000, 162(1), 105-111) and is considered important in CD4+ cell migration. Cowden et al (Respir Res, 2010; 11:86) showed that blockade of the H4 receptor inhibited T cell infiltration into the lung and decreased Th2 cytokines IL-13 and IL-5. Additionally, improvement in measures of central and peripheral airway dysfunction were shown with H4 antagonists (Alfon, et al., Inflamm Res, 2010; 59 (Suppl 2): S199-200).
There has also been evidence that the histamine H4 receptor (H4R) mediates pruritus in mice, but via a different mechanism from the histamine H1 receptor (H1R), and therefore it may play a role in pruritic responses in atopic dermatitis. In mice, histamine and selective histamine H4R agonists caused scratching responses, which were almost completely abolished in H4R knockout mice or by pretreatment with an H4R antagonist, Yu, F. et al., Journal of Receptor, Ligand and Channel Research 3, 37-49 (2010); Dunford, P. J. et al., Journal of Allergy and Clinical Immunology 119, 176-183 (2007); Bell, J. K., et al., British Journal of Pharmacology 142, 374-380 (2004)). Differential roles for the H1R and H4R were observed in mouse models where scratching behavior was induced by histamine or substance P. The H1R antagonist, fexofenadine, reduced scratching induced by histamine but not by substance P, whereas the same H4R antagonist significantly reduced both histamine- and substance P-induced scratching, (Yamaura, K, et al., Journal of Toxicological Sciences 34, 427-431 (2009)). In addition, the same antagonist was shown to be effective in reducing hapten-induced scratching behavior and scratching to IgE-mediated mast cell degranulation. (Dunford, P. J. et al., Journal of Allergy and Clinical Immunology 119, 176-183 (2007); Rossbach, K. et al., Experimental Dermatology 18, 57-63 (2009). The same was seen in the mouse model of atopic dermatitis where scratching to the hapten was reduced by H4R antagonist treatment. (Cowden, J. M., et al., Journal of Investigative Dermatology (2009)).
Therefore, based on the above mentioned experimental results, it may be envisaged that H4R antagonists may have utility for the treatment of itch associated with a variety of conditions such as atopic dermatitis eczema, urticaria (hives), psoriasis, oncological conditions such as T cell lymphoma, itch associated with the administration of drugs to treat parasitic or fungal infections (e.g., lice, scabies, swimmer's itch, jock itch, athlete's foot), hidradenitis suppurativa, malignancy/lymphoma (e.g., Hodgkin's disease), jaundice, polycythemia, punctate palmoplantar keratoderma, thyroid illness/hyperparathyroidism, diabetes, primary biliary cirrhosis, chicken pox, iron deficiency anemia, psychiatric diseases, medication-induced cholestasis; pregnancy-related cholestasis (e.g., obstetric cholestasis), pruritic urticaria papules and plaques of pregnancy, gestational phemphigoid; xerosis (dry skin), sunburn, dandruff, scab/scars, insect bites, poison ivy/oak, hemorrhoids, contact dermatitis, old-age associated itch, and itch associated with dialysis.
Recent work has shown that the H4 receptor and/or H4 modulators (agonists or antagonists) may play a role in a diverse array of medical conditions and diseases. (Kiss, R. and Keseru, G. M., Expert Opin. Ther. Patents, 2012, 22(3), 205-221) Several of which are listed below. The treatment of choroidal neovascularization in age-related macular degeneration (AMD) using H4 antagonists has been investigated. (Ye, F. et al. 2014 ARVO Meeting Abstract, Program #3291, Board #C0223, Histamine Receptor H4 as a New Therapeutic Target for Choroidal Neovascularization in Age-related Macular Degeneration). The H4 receptor was also found to be highly expressed in stromal inflammation cells in vernal keratoconjuctivitis (Leonardi, A. et al., Allergy, 2011, 66, 1360-1366.) In addition, studies using H4 antagonists for the treatment of post-operative adhesions were conducted (WO2009152287), and research on the role of H4 receptors and modulators in cancer, for example melanoma, breast cancer and colorectal carcinomas (Massari, N. A. et al. Melanoma Res, 2011, 21, 395-404; Medina, V. A. et al., Front Biosci (Elite Ed), 2011, 3, 1042-1060; Fang, Z. et al., BMC Cancer, 2011, 11:195, 1-11) have also been performed. In a mouse model of sepsis, expression of the H4 receptor gene was significantly up-regulated in key organs including the spleen, implicating a potential therapeutic role of H4 antagonists in the treatment of sepsis. (Matsuda, N., et al., J. Pharmacol. Exp. Ther, 2010, 332, 730-737.) It has also been theorized that H4 antagonists may be administered with a long acting β-agonist, acting in a synergistic manner to improve lung functions and in the treatment of asthma.
Numerous pro-inflammatory cytokines have been increasingly reported to be elevated in patients suffering of major depression, when compared with non-depressed subjects or, in some cases, correlated with symptom severity. (Frommberger et al., European Archives of Psychiatry & Clinical Neuroscience. 1997, 247(4), 228-33; Sluzewska A., et al., Psychiatry Research, 1996, 64(3), 161-7; Ortiz-Dominguez, et al., Bip. Disorder 9, 2007; O'Brien, et al., J. Affective Disorders, 2006, 90, 263-267; Anisman H. et al., Biological Psychiatry, 1999, 46(12),1649-55) These include increased acute-phase proteins (Kling et al., Biol. Psychiatry, 2007, 62, 309-313; Kim et al., Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2007, 31, 1044-1053; (C-reactive protein, α-1-acid glycoprotein, α-1-antichymotrypsin and haptoglobin), increased expression of chemokines and adhesion molecules (including human macrophage chemoattractant protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1) and E-selectin), and increased serum and/or plasma concentrations of interleukin(IL)-1-β, IL-6, and tumor necrosis factor (TNF)-α, both in the peripheral blood circulation and in the central nervous system (particularly in the cerebrospinal fluid) with a higher level of consistency when measuring TNF-α and IL-6 (O'Brien et al., Journal of Psychiatric Research, 2007, 41, 326-331; Moorman et al., J. of Cardiac Failure, 2007, 13(9), 738-43; Soygur et al., Progress in Neuro-Psychopharmacology & Biolofical Psychiatry, 2007, 31, 1242-1247). Additionally, allelic variants of the genes for IL-1β and TNF-α increase the risk for depression and are associated with reduced responsiveness to antidepressant therapy. Finally, there is available preclinical evidence supporting the involvement of several cytokines in models of depression and some clinical evidence of the involvement of cytokines antagonism in the treatment of depressive symptoms on patients suffering from active inflammatory diseases (Kim et al., (2007)).
Thus, based at least inpart on citations above, it is envisaged that H4 antagonists may have antidepressant and/or anxiolytic properties suitable for the treatment of mood disorders (including but not limited to Major Depressive Disorder, Bipolar Disorder, Treatment Resistant Major Depressive Disorder and Treatment Resistant Bipolar Disorder), anxiety disorders (including but not limited to Generalized Anxiety Disorder, Social Phobia, and post traumatic stress disorder).
Modulation of the histamine H4 receptor has also been implicated in the treatment of pain (Intl. Pat. Appl. Publ. WO 2008/060766 (Abbott). The H4R has been shown to be expressed in the CNS, including the brain, spinal cord, and dorsal root ganglia. (Strakhova, M. I. et al., Brain Research 1250, 41-48 (2009)). H4R antagonists have been shown to possess antinociceptive activity in several models of pain. (Altenbach, R. J., et al., J. Med. Chem. 51, 6571-6580 (2008); Coruzzi, G., et al., European Journal of Pharmacology 563, 240-244 (2007); Cowart, M. D. et al., J. Med. Chem. 51, 6547-6557 (2008); Hsieh, G. C. et al., Pharmacol. Biochem. Behav. 95, 41-50 (2010)). The H4R antagonist given in example 1, U.S. Pat. No. 6,803,362, was as efficacious as diclofenac in an acute carrageenan-induced inflammatory pain model and in a more chronic CFA-induced pain model. (Hsieh, G. C. et al., (2010)). Similar results were seen in a model of osteoarthritis where the maximum efficacy was on par with celecoxib and in a model of post-operative pain where the efficacy approached that of morphine. (Hsieh, G. C. et al., (2010)). Activity for a number of compounds has been reported in neuropathic pain models including an antagonist wherein the efficacy was superior to that of gabapentin in two different models. (Cowart, M. D. et al., (2008); Hsieh. G. C. et al., (2010)). In addition, selective H4R antagonists significantly reduced paw edema and hyperalgesia provoked by subplantar injection of carrageenan in a rat acute inflammation and hyperalgesia model. (Coruzzi, G., et al., (2007); Liu, H. et al., J. Med. Chem. 51, 7094-7098 (2008)). These data support the claims that H4R antagonist may have utility in the treatment of nociceptive and/or neuropathic pain.
Adiposity-associated inflammation and insulin resistance are associated with the development of type II diabetes, fatty liver and atherosclerosis. The role of the H4 receptor and its ligands in these conditions has been explored. (Gill, D. S. Diabetes Research, 1988, 7(1), 31-34; Rosa, A. C., Inflammation Research, 2013, 62(4), 357-365). Macrophages are recruited into adipose tissue and atherosclerotic plaques, and are activated to release inflammatory cytokines and chemokines. High fat diets associated with the development of these conditions may lead to increased gut permeability and dyslipidemia. Consequent toll-ligand receptor, 2 and 4 (TLR2, TLR4) activation of adipocytes and macrophages by bacteria and by high levels of free fatty acids leads to an inflammatory phenotype and insulin resistance. Specifically, insulin signaling pathways may be attenuated by cytokines such as TNFα and IL-6 and activation of kinases including c-jun kinase, NKkB or PKCθ, downstream of TLR2/4 stimulation. Effects on insulin receptor signaling are potentiated by increased infiltration of monocyte/macrophages into the tissue by release of chemokines such as MCP-1.
H4R is a high affinity receptor for histamine expressed on monocyte/macrophage populations and other hematopoietic cells. Antagonism of the H4R has been shown to reduce TLR4 signaling in vitro and to reduce TLR2 and TLR4 mediated inflammatory cytokine production in vitro and in vivo. Levels of pro-inflammatory mediators including TNF-α, IL-6 and LTB4 have been variously shown to be inhibited by H4R antagonism in TLR dependent systems.
Examples of textbooks on the subject of inflammation include: 1) Gallin, J. I.; Snyderman, R., Inflammation: Basic Principles and Clinical Correlates, 3rd ed.; Lippincott Williams & Wilkins: Philadelphia, 1999; 2) Stvrtinova, V., et al., Inflammation and Fever. Pathophysiology Principles of Diseases (Textbook for Medical Students); Academic Press: New York, 1995; 3) Cecil; et al, Textbook Of Medicine, 18th ed.; W.B. Saunders Co., 1988; and 4) Stedman's Medical Dictionary.
Background and review material on inflammation and conditions related with inflammation can be found in articles such as the following: Nathan, C., Nature 2002, 420(6917), 846-852; Tracey, K. J., Nature 2002, 420(6917), 853-859; Coussens, L. M., et al., Nature 2002, 420(6917), 860-867; Libby, P., Nature 2002, 420, 868-874; Benoist, C., et al., Nature 2002, 420(6917), 875-878; Weiner, H. L., et al., Nature 2002, 420(6917), 879-884; Cohen, J., Nature 2002, 420(6917), 885-891; Steinberg, D., Nature Med. 2002, 8(11), 1211-1217.